chr11-17547466-G-T

Variant names:

• chr11-17547466-G-T
• rs565203765
• NM_001292063.2:c.94G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001292063.2(OTOG):​c.94G>T​(p.Ala32Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000246 in 1,217,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A32T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04
• Publications: 1 publications found

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.94G>T	p.Ala32Ser	missense_variant, splice_region_variant	Exon 1 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.94G>T	p.Gly32Cys	missense_variant	Exon 1 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.94G>T	p.Ala32Ser	missense_variant, splice_region_variant	Exon 1 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.94G>T	p.Gly32Cys	missense_variant	Exon 1 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000246 AC: 3 AN: 1217442 Hom.: 0 Cov.: 31 AF XY: 0.00000338 AC XY: 2 AN XY: 591432

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24590

American (AMR) AF: 0.0000684 AC: 1 AN: 14628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17230

East Asian (EAS) AF: 0.00 AC: 0 AN: 28518

South Asian (SAS) AF: 0.0000193 AC: 1 AN: 51928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4938

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 998340

Other (OTH) AF: 0.00 AC: 0 AN: 49958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.022510), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T
PhyloP100		2.0
Sift4G	Benign	0.34	T
Vest4		0.22
MVP		0.072
ClinPred		0.76	D
GERP RS		3.3
PromoterAI		-0.079	Neutral
Varity_R		0.16
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -39
DS_DL_spliceai		0.62		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs565203765; hg19: chr11-17569013;